Retinoic acid and other retinoids are able to control cellular differentiation and, by so doing, are able to suppress or reverse the transformation of premalignant cells to the malignant state. Therefore, the retinoids have potential value as therapeutic and prophylactic agents for the treatment of cancer if their toxic side effects can be reduced. We propose to synthesize and screen potentially more effective retinoids to develop drugs having an improved therapeutic index (ratio of tumor-inhibitory activity to toxicity). In particular, we propose systematic structure-activity studies of analogs of four active retinoids that we have synthesized--namely, (1) 4-[(E)-2-(4,4-dimethyl-3,4-dihydro-2H-1-benzopyran-6-yl)-propenyl]benzoic acid, (2) 4-[(E)-2-(4,4-dimethyl-3,4-dihydro-2H-1-benzothiopyran-6-yl)-propenyl]benzoi cacid, (3) 4-[(E)-2-(4,4-dimethyl-4,5,6,7-tetrahydro-2-benzo[b]-thienyl)propenyl]benzoi cacid, and (4) 6-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-6-naphthyl)-2-naphthalenecarboxyli cacid--to further determine what regions of the retinoid skeleton enhance tumor-inhibitory activity and reduce toxicity. Compounds will first be tested in three rapid, preliminary screens used to assess retinoid activity: (1) the reversal of keratinization in retinoid-deficient epithelial cells of hamster trachea in organ culture, (2) the inhibition of the induction of ornithine decarboxylase in mouse epidermis treated with a tumor promoter, and (3) the induction of differentiation of F9 murine embryonic carcinoma cells. Active retinoids will then be screened in two in vivo assays to determine (1) their effectiveness in inhibiting papilloma tumor formation in mouse epidermis treated with a carcinogen and a tumor promoter (antipapilloma assay) and (2) their toxicity in the mouse (hypervitaminosis A assay). The therapeutic index will be determined from these two assays. This approach should lead to the design and synthesis of more effective retinoids. In addition, we propose the synthesis of radiolabeled, photoaffinity-labeled retinoids to probe the biochemical mechanism and site of retinoid action.